Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is a triazole antifungal drug represented by the structure:

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species, Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents. One of the important intermediates for the preparation of posaconazole is the compound of formula (V)
in particular the compound of formula (V) with R1=ethyl

To date, no process has been known which affords the compound of formula (V), in particular the compound of formula (V) with R1=ethyl, especially in high enantiomeric, diastereomeric purity and yield. Only the corresponding benzyl protected compound shown below has been described in the literature until now. Unfortunately, the compound of formula (V) with R1=ethyl is not readily accessible via deprotection of the benzyl protected derivative using standard hydrogenolytic conditions.
A common intermediate in the process for preparing posaconazole is a compound of formula

A process for the preparation of this intermediate is disclosed in WO 95/17407. The overall yield of this process is approximately 25%, and the diastereomeric purity with regard to the isomer of formula
is in the range of from 94-99%, with the enantiomeric purity depending on the quality of the starting material lactic methyl ester. WO 95/17407 is completely silent on a purification of said intermediate.
WO 97/22579 and Saksena et al., Tetrahedron Lett. 2004, 45 (44), 8249-8251, disclose improved processes for the Grignard reaction carried out in the course of the reaction sequence described in WO 95/17407. A silylation step and addition of tert-BuMgCl to the Grignard reaction is described to afford the intermediate with a purity of 95% without using an additional purification by chromatography. However, the inventors of the present invention, although high-skilled technical experts in this specific chemical area, were not able to reproduce these results. No matter which reasonable modification of the teaching of WO 97/22579 and Saksena et al. was made, the intermediate was always obtained as a complicated mixture which had to be subjected to double chromatography in order to reach the claimed purity.
A further process disclosed in WO 96/33163 involves stereochemical resolution of an intermediate via salt formation using chiral acids (e.g. dibenzoyl-L-tartaric acid, L-DBTA) and crystallization of the obtained diastereomeric salts in order to obtain the above-described intermediate in high optical purity. Yet another process, disclosed in WO 97/33178, requires protection of one hydrazine nitrogen in order to introduce the chiral center by reduction with costly reagents with a selectivity of 0-94% with regard to the desired isomer. Neither in WO 96/33163 nor in WO 97/33178 a purification of the products is described, except for the stereochemical resolution.
All these methods of the prior art suffer from significant drawbacks.
First, the described approaches share the requirement of an OH protecting group both during the synthesis of an intermediate hydrazide and for the subsequent preparation of antifungal agents. In addition, harsh reaction conditions along the synthesis pathways may be regarded as being prohibitive for widely used protecting groups, including silyl ethers and esters. It is believed that solely ethers are stable enough which may be the reason why in all concrete examples, only benzyl ether is consistently disclosed.
Second, none of these processes of the prior art allows for a direct preparation of an unprotected compound of formula (V) and, for example, a subsequent protection of the OH group of the compound of formula (V) with a desired protecting group tailor-made for subsequent reactions.
Third, as mentioned above, elaborate purification of the oily products by either chromatography or stereochemcial resolution is required to counterbalance the insufficient chemo selectivity and stereoselectivity of the reaction pathways of the prior art.
Fourth, multiple oxidation state adjustments on the reaction pathways of the prior art, including a large excess of expensive reagents, increase the number of individual steps and lower the overall yield. These shortcomings considerably decrease the yield of the desired hydrazide of formula (V) and in particular of formula (V) with R1=ethyl
and respectively protected derivatives thereof. At the same time large amount of undesired waste products are obtained, making the prior art process even more disadvantageous.
Therefore, it was an object of the present invention to provide an efficient process for the production of chiral hydrazides, in particular for the production of a compound of formula (V) with R1=ethyl
which may be advantageously used as intermediate for the production of azole antifungal agents, in particular posaconazole.
It was a further object of the present invention to provide an efficient process for the preparation of a crystalline compound of formula (V) and in particular of formula (V) with R1=ethyl
and, further, for compounds based on this crystalline compound suitably protected at the OH group.
It was a further object of the present invention to provide said crystalline compound as such, as well as said suitably protected compounds.
Surprisingly, it was found that above-discussed objects are met by a process wherein, in a first stage, a compound of formula
with Y being an optionally substituted aryl moiety is provided and reacted with H2N—NH—CHO in a suitable solvent from which a chiral compound of formula
is obtained.